Development of the Binocular Circuit

Abstract

Seeing in three dimensions is a major property of the visual system in mammals. The circuit underlying this property begins in the retina, from which retinal ganglion cells (RGCs) extend to the same or opposite side of the brain. RGC axons decussate to form the optic chiasm, then grow to targets in the thalamus and midbrain, where they synapse with neurons that project to the visual cortex. Here we review the cellular and molecular mechanisms of RGC axonal growth cone guidance across or away from the midline via receptors to cues in the midline environment. We present new views on the specification of ipsi- and contralateral RGC subpopulations and factors implementing their organization in the optic tract and termination in subregions of their targets. Lastly, we describe the functional and behavioral aspects of binocular vision, focusing on the mouse, and discuss recent discoveries in the evolution of the binocular circuit.

Keywords: axon targeting; ciliary margin; evolution; optic chiasm; retinal ganglion cell; transcriptomics.

Figure 1

Wnt5a-dependent regulation of RGC axonal divergence at the chiasm midline. As RGC axons reach the midline, they encounter Wnt5a. All RGC axons express Wnt receptors (i.e., Fz). Upon binding to Wnt5a, Fz receptors trigger local accumulation of β-catenin, a key protein that connects α-catenin, cadherins, and actin filaments. The formation and stabilization of catenin/cadherin complexes promote the polymerization of actin filaments and implement forward growth of the axon, for contralateral RGCs (top). In ipsilateral RGCs (bottom), the presence of the tyrosine kinase receptor EphB1, expressed only in ipsilateral RGCs, comes into play: Upon binding to ephrin-B2, also expressed by midline cells, EphB1 can locally phosphorylate β-catenin at Y654 (Y654-β-catenin, purple circles). The phosphorylated form of β-catenin has reduced affinity for cadherins, hampering the formation of cadherin/actin complexes that produce forward growth. The nonphosphorylated excess β-catenin promotes cytoskeleton stabilization in the aspect of the growth cone interacting with midline cells and stimulates axon steering away from the midline. In addition to the shared Wnt receptors expressed by both RGC subpopulations, ipsilateral RGCs also express other Wnt receptors, including Lgr5, Fz1, and Fz8, which may also contribute to the act of growth cone turning. Abbreviations: EphB1, ephrin type B receptor 1; Fz, frizzled; Lgr5, leucine-rich repeat-containing G protein–coupled receptor 5; MT, microtubule; RGC, retinal ganglion cell.

Figure 2

Regulatory transcriptional networks underlying contralateral/ipsilateral RGC identity. All retinal neuronal progenitors express Atoh7 before differentiating into RGCs. Although the trigger is not known, some progenitors begin to express Pou3f1, which then represses the expression of Atoh7 and promotes neuronal differentiation. The expression of Pou3f1 induces the contralateral gene program, including Pou4f1 and SoxCs, which in turn controls the expression of Notch1 and Hes5. In contrast, recently differentiated ipsilateral neurons express Zic2, which may repress Pou3f1 and possibly Pou4f1, inhibiting the contralateral program and stimulating the expression of a series of receptors (EphB1, Fzd1, Fzd8, Lgr5) that promote repulsion from the midline. It is not clear whether Zic2 also represses Atoh7 directly or via Pou3f1 to ensure ipsilateral identity. The Lhx family (not shown) may also play a role in regulating the ipsilateral pathway by modulating the expression of Zic2 targets involved in Wnt signaling, although it is unclear whether these transcription factors are switched on by Zic2 or act as independent cofactors. Abbreviations: Atoh7, atonal BHLH transcription factor 7; Bmpr1, bone morphogenetic protein receptor type 1; EphB1, Eph receptor B1; Fz, frizzled; Hes5, Hes family BHLH transcription factor 5; Lgr5, leucine-rich repeat-containing G protein–coupled receptor 5; Lhx, LIM homeobox transcription factor; Notch1, Notch receptor 1; NrCam, neuronal cell adhesion molecule; Nrp1, neuropilin 1; Pou3f1, POU class 3 homeobox 1; Plxn1, plexin A1; RGC, retinal ganglion cell; Zic2, zinc finger protein of the cerebellum 2.

Figure 3

Evolution of visual projection binocularity. (a) Simplified phylogenetic tree of jawed vertebrates. Most teleost lineages lack ipsilateral visual projections, but eyes project bilaterally in other jawed vertebrates, including cartilaginous fishes, most basal ray-finned fishes, and lobe-finned fishes. Visual projections are also bilateral in tetrapods but have been charted only in a few bird species during development. (b) Diagrams of visual system connectivity in a teleost, two nonteleosts (gar and lungfish), and a tetrapod. Left and right retinal projections are shown in orange and blue, respectively. Figure adapted with permission from Vigouroux et al. (2021).